Impaired Amyloid Beta Clearance and Brain Microvascular Dysfunction are Present in the Tg-SwDI Mouse Model of Alzheimer's Disease. (1st August 2020)

• Record Type: Journal Article
• Authors: Rosas-Hernandez, Hector; Cuevas, Elvis; Raymick, James B.; Robinson, Bonnie L.; Sarkar, Sumit
• Is Part Of: Neuroscience. Volume 440(2020)
• Page Start: 48
• Page End: 55
• Publication Date: 2020-08-01
• Subjects: AD Alzheimer's disease -- Aβ amyloid beta -- BBB blood–brain barrier -- BMVECs brain microvascular endothelial cells -- CAA cerebral amyloid angiopathy -- NFTs neurofibrillary tangles -- RAGE receptor for advance glycation end-products -- TJs tight junction -- WT wild type; Alzheimer's disease -- blood–brain barrier -- tight junctions -- amyloid beta (Aβ) -- Aβ transporters -- permeability; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2020.05.024
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Tg-SwDI mice accumulate Aβ aggregates in their brain microvessels. Tg-SwDI mice's microvessels have decreased levels of P-gp and increased RAGE levels. Tg-SwDI mice's microvessels present lower levels of occludin. Tg-SwDI mice's brain endothelial cells present increased paracellular permeability. Abstract: Alzheimer's disease (AD) pathology is characterized by amyloid plaques containing amyloid beta (Aβ) peptides, neurofibrillary tangles containing hyperphosphorylated tau protein, and neuronal loss. In addition, Aβ deposition in brain microvessels, known as cerebral amyloid angiopathy (CAA), increases blood–brain barrier (BBB) permeability and induces vascular dysfunction which aggravates AD pathology. The aim of the present study was to characterize neurovascular dysfunction in the Tg-SwDI mouse model of AD. Isolated brain capillaries from wild type (WT) and Tg-SwDI mice were used to evaluate the expression of monomeric and aggregated forms of Aβ, P-glycoprotein (P-gp), the receptor for advance glycation end-products (RAGE) and the tight junction (TJs) proteins occludin and claudin-5. Cultured brain endothelial cells were used to analyze barrier function via fluorescein flux. Isolated capillaries from Tg-SwDI mice contained increased levels of aggregated and oligomeric Aβ compared to WT animals. Isolated capillaries from Tg-SwDI had decreased levels of P-gp, which transports Aβ from brain to blood, and increased levels of RAGE, which transports Aβ from blood to brain. In addition, the TJ protein occludin was decreased in Tg-SwDI mice relative to WT mice, which correlated with an increase in BBB permeability in cultured brain endothelial cells. These findings demonstrated that Tg-SwDI mice exhibit Aβ aggregation that is due, in part, to impaired Aβ clearance driven by both a decrease in P-gp and increase in RAGE protein levels in brain capillaries. Aβ aggregation promotes a decrease in the expression of the TJ protein occludin, and as consequence an increase in BBB permeability.